RESUMO
Malan syndrome is an overgrowth disorder described in a limited number of individuals. We aim to delineate the entity by studying a large group of affected individuals. We gathered data on 45 affected individuals with a molecularly confirmed diagnosis through an international collaboration and compared data to the 35 previously reported individuals. Results indicate that height is > 2 SDS in infancy and childhood but in only half of affected adults. Cardinal facial characteristics include long, triangular face, macrocephaly, prominent forehead, everted lower lip, and prominent chin. Intellectual disability is universally present, behaviorally anxiety is characteristic. Malan syndrome is caused by deletions or point mutations of NFIX clustered mostly in exon 2. There is no genotype-phenotype correlation except for an increased risk for epilepsy with 19p13.2 microdeletions. Variants arose de novo, except in one family in which mother was mosaic. Variants causing Malan and Marshall-Smith syndrome can be discerned by differences in the site of stop codon formation. We conclude that Malan syndrome has a well recognizable phenotype that usually can be discerned easily from Marshall-Smith syndrome but rarely there is some overlap. Differentiation from Sotos and Weaver syndrome can be made by clinical evaluation only.
Assuntos
Anormalidades Múltiplas/genética , Hipotireoidismo Congênito/genética , Anormalidades Craniofaciais/genética , Deformidades Congênitas da Mão/genética , Deficiência Intelectual/genética , Fatores de Transcrição NFI/genética , Síndrome de Sotos/genética , Anormalidades Múltiplas/fisiopatologia , Adolescente , Adulto , Doenças do Desenvolvimento Ósseo/genética , Doenças do Desenvolvimento Ósseo/fisiopatologia , Criança , Pré-Escolar , Deleção Cromossômica , Hipotireoidismo Congênito/fisiopatologia , Anormalidades Craniofaciais/fisiopatologia , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/fisiopatologia , Éxons/genética , Feminino , Deformidades Congênitas da Mão/fisiopatologia , Humanos , Deficiência Intelectual/fisiopatologia , Masculino , Megalencefalia/genética , Megalencefalia/fisiopatologia , Mutação de Sentido Incorreto/genética , Fenótipo , Displasia Septo-Óptica/genética , Displasia Septo-Óptica/fisiopatologia , Síndrome de Sotos/fisiopatologia , Adulto JovemRESUMO
BACKGROUND: Congenital anomalies of the kidney and urinary tract (CAKUT) represent a significant healthcare burden since it is the primary cause of chronic kidney in children. CNVs represent a recurrent molecular cause of CAKUT but the culprit gene remains often elusive. Our study aimed to define the gene responsible for CAKUT in patients with an 1q23.3q24.1 microdeletion. METHODS: We describe eight patients presenting with CAKUT carrying an 1q23.3q24.1 microdeletion as identified by chromosomal microarray analysis (CMA). Clinical features were collected, especially the renal and urinary tract phenotype, and extrarenal features. We characterised PBX1 expression and localisation in fetal and adult kidneys using quantitative RT-PCR and immunohistochemistry. RESULTS: We defined a 276-kb minimal common region (MCR) that only overlaps with the PBX1 gene. All eight patients presented with syndromic CAKUT. CAKUT were mostly bilateral renal hypoplasia (75%). The most frequent extrarenal symptoms were developmental delay and ear malformations. We demonstrate that PBX1 is strongly expressed in fetal kidneys and brain and expression levels decreased in adult samples. In control fetal kidneys, PBX1 was localised in nuclei of medullary, interstitial and mesenchymal cells, whereas it was present in endothelial cells in adult kidneys. CONCLUSIONS: Our results indicate that PBX1 haploinsufficiency leads to syndromic CAKUT as supported by the Pbx1-null mice model. Correct PBX1 dosage appears to be critical for normal nephrogenesis and seems important for brain development in humans. CMA should be recommended in cases of fetal renal anomalies to improve genetic counselling and pregnancy management.
Assuntos
Haploinsuficiência/genética , Fator de Transcrição 1 de Leucemia de Células Pré-B/genética , Anormalidades Urogenitais/genética , Refluxo Vesicoureteral/genética , Criança , Pré-Escolar , Feminino , Feto/metabolismo , Genoma Humano , Humanos , Lactente , Rim/anormalidades , Rim/embriologia , Rim/metabolismo , Rim/patologia , Masculino , SíndromeRESUMO
5q11.2 Deletion is a very rare genomic disorder, and its clinical phenotype has not yet been characterized. This report describes a patient with an 8.6 Mb deletion, showing hypotonia, mild developmental delay, short stature, and distinctive dysmorphic features (frontal bossing, square face, deep-set eyes, prominent columella, long philtrum, thin lips). © 2016 Wiley Periodicals, Inc.
Assuntos
Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Deleção Cromossômica , Cromossomos Humanos Par 5 , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/genética , Fenótipo , Encéfalo/anormalidades , Ecocardiografia , Estudos de Associação Genética , Humanos , Lactente , Imageamento por Ressonância Magnética , Masculino , Síndrome , UltrassonografiaRESUMO
BACKGROUND: Loss-of-function mutations of the FLNA gene cause a neuronal migration disorder defined as X-linked periventricular nodular heterotopia (PNH); gain-of-function mutations are associated with a group of X-linked skeletal dysplasias designed as otopalatodigital (OPD) spectrum. We describe a family in which a woman and her three daughters exhibited a complex phenotype combining PNH, epilepsy and Melnick-Needles syndrome (MNS), a skeletal disorder assigned to the OPD spectrum. All four individuals harboured a novel non-conservative missense mutation in FLNA exon 3. METHODS: In all affected family members, we performed mutation analysis of the FLNA gene, RT-PCR, ultradeep sequencing analysis in FLNA cDNAs and western blot in lymphocyte cells to further characterise the mutation. We also assessed the effects on RT-PCR products of treatment of patients' lymphocytes with cycloheximide, a nonsense mediated mRNA decay (NMD) inhibitor. RESULTS: We identified a novel c.622G>C change in FLNA exon 3, leading to the substitution of a highly conserved aminoacid (p.Gly208Arg). Gel electrophoresis and ultradeep sequencing revealed the missense mutation as well as retention of intron 3. Cycloheximide treatment demonstrated that the aberrant mRNA transcript-retaining intron 3 is subjected to NMD. Western blot analysis confirmed reduced FLNA levels in lymphocyte cells. CONCLUSIONS: The novel c.622G>C substitution leads to two aberrant FLNA transcripts, one of which carries the missense mutation, plus a longer transcript resulting from intron 3 retention. We propose that the exceptional co-occurrence of PNH and MNS, two otherwise mutually exclusive allelic phenotypes, is the consequence of a single mutational event resulting in co-occurring gain-of-function and loss-of-function effects.
Assuntos
Epilepsia/genética , Filaminas/genética , Estudos de Associação Genética , Mutação , Osteocondrodisplasias/genética , Heterotopia Nodular Periventricular/genética , Sequência de Bases , Osso e Ossos/diagnóstico por imagem , Osso e Ossos/patologia , Encéfalo/patologia , Biologia Computacional , Análise Mutacional de DNA , Éxons , Feminino , Filaminas/química , Filaminas/metabolismo , Genes Ligados ao Cromossomo X , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Linfócitos/metabolismo , Imageamento por Ressonância Magnética , Dados de Sequência Molecular , Mutação de Sentido Incorreto , Degradação do RNAm Mediada por Códon sem Sentido , Osteocondrodisplasias/diagnóstico , Linhagem , Heterotopia Nodular Periventricular/diagnóstico , Splicing de RNA , Radiografia , Alinhamento de Sequência , Síndrome , Inativação do Cromossomo XRESUMO
OBJECTIVE: To evaluate an in vivo pro-oxidant state in patients with ataxia telangiectasia (AT). METHODS: A set of oxidative stress endpoints were measured in 9 AT homozygotes, 16 AT heterozygotes (parents) and 83 controls (grouped in age ranges as for patients and parents, respectively). The following analytes were measured: (a) leukocyte 8-hydroxy-2'-deoxyguanosine (8-OHdG); (b) blood glutathione (GSSG and GSH); and (c) plasma levels of glyoxal (Glx) and methylglyoxal (MGlx). RESULTS: AT patients displayed a significant decrease in blood GSSG (p=0.012) and in MGlx plasma concentrations (p=0.012). A non-significant decrease in the GSSG:GSH ratio (p=0.1) and a non-significant increase in 8-OHdG and Glx levels were observed in AT patients vs. young controls (age range 4-35 years). AT heterozygotes failed to display any significant changes vs. adult controls (age range 36-68 years). CONCLUSION: No significant increase in oxidative stress biomarkers was detected in blood from AT patients. The decrease in GSSG and MGlx levels in AT patients may suggest an adaptive response to a pro-oxidant state in AT-related target organs.
Assuntos
Ataxia Telangiectasia/sangue , Glutationa/sangue , Estresse Oxidativo/fisiologia , 8-Hidroxi-2'-Desoxiguanosina , Adaptação Fisiológica , Adolescente , Adulto , Criança , Pré-Escolar , Dano ao DNA , Desoxiguanosina/análogos & derivados , Desoxiguanosina/sangue , Feminino , Glioxal/sangue , Humanos , Masculino , Aldeído Pirúvico/sangueRESUMO
Brachydactyly type E is a congenital limb malformation characterized by small hands and feet as a result of shortened metacarpals and metatarsals. Genetic causes of this anomaly are heterogeneous and only partially characterized. In this report we describe an Italian family in which four subjects share brachydactyly type E and a 3 Mb microduplication in region 6p25. The duplication involves the gene FOXC1, expressed during the osteoblast differentiation, which appears a potential candidate gene for brachydactyly.
Assuntos
Braquidactilia/genética , Fatores de Transcrição Forkhead/genética , Trissomia/genética , Adulto , Cromossomos Humanos Par 6/genética , Feminino , Humanos , Lactente , Itália , Cariótipo , Ossos Metacarpais/anormalidades , Ossos do Metatarso/anormalidades , Pessoa de Meia-IdadeRESUMO
The Nuclear Factor I-X (NFIX) is a member of the nuclear factor I (NFI) protein family and is deleted or mutated in a subset of patients with a peculiar overgrowth condition resembling Sotos Syndrome as well as in patients with Marshall-Smith syndrome. We identified three additional patients with this phenotype each carrying a different new mutation affecting the DNA-binding/dimerization domain of the NFIX protein. The present report further adds weight to the hypothesis that mutations in DNA-binding/dimerization domain are likely to cause haploinsufficiency of the NFIX protein and confirms that NFIX is the second gene that should be tested in individuals with overgrowth conditions resembling Sotos syndrome, previously tested negative for NSD1 mutations. We then propose to consider this overgrowth syndrome (namely Malan syndrome) and Marshall-Smith syndrome NFIX-related diseases.
Assuntos
Anormalidades Múltiplas/genética , Doenças do Desenvolvimento Ósseo/genética , Anormalidades Craniofaciais/genética , Proteínas de Ligação a DNA/genética , Fatores de Transcrição NFI/genética , Displasia Septo-Óptica/genética , Síndrome de Sotos/genética , Anormalidades Múltiplas/diagnóstico , Doenças do Desenvolvimento Ósseo/diagnóstico , Criança , Anormalidades Craniofaciais/diagnóstico , Proteínas de Ligação a DNA/metabolismo , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/genética , Feminino , Testes Genéticos , Histona Metiltransferases , Histona-Lisina N-Metiltransferase , Humanos , Lactente , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Masculino , Mutação de Sentido Incorreto , Fatores de Transcrição NFI/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Fenótipo , Displasia Septo-Óptica/diagnóstico , Síndrome de Sotos/diagnósticoRESUMO
The 22q11.2 microduplication is a genomic disorder, characterized from a variable phenotype ranging from different defects to normality. The most common microduplication of 22q11.2 is 3 Mb in size, but there are also cases reported with atypical duplications between 0.8 Mb and 6Mb. Here, we describe a case of a child with macrocephaly, overgrowth with advanced bone age, attention deficits, evidence of mild mental retardation and dysmorphic features. An array-CGH analysis detected a 252 Kb duplication at the 22q11.2 region inherited from mother and 142 Kb duplication at 8q22.1 region inherited from father. Both parents show mild dysmorphic features. The duplicated genes in chromosomes 22q and 8q are TOP3B and PGCP, respectively. We describe for the first time a patient carrying the smaller atypical 22q11.2 duplication who also presents with mild mental retardation and generalized overgrowth. This patient has an additional duplication in 8q22.1 which may act as a genomic modifier of its clinical phenotype.
Assuntos
Anormalidades Múltiplas/genética , Duplicação Cromossômica/genética , Síndrome de DiGeorge/genética , Transtornos do Crescimento/genética , Deficiência Intelectual/genética , Trissomia/genética , Adolescente , Adulto , Cromossomos Humanos Par 22/genética , Cromossomos Humanos Par 8/genética , Feminino , Humanos , MasculinoRESUMO
Oxidative stress has been associated with Down syndrome (DS) and with its major phenotypic features, such as early ageing. In order to evaluate an in vivo pro-oxidant state, the following analytes were measured in a group of DS patients aged 2 months to 57 years: (a) leukocyte 8-hydroxy-2'-deoxyguanosine (8-OHdG); (b) blood glutathione; (c) plasma levels of: glyoxal (Glx) and methylglyoxal (MGlx); some antioxidants (uric acid, UA, ascorbic acid, AA and Vitamin E), and xanthine oxidase (XO) activity. A significant 1.5-fold increase in 8-OHdG levels was observed in 28 DS patients vs. 63 controls, with a sharper increase in DS patients aged up to 30 years. The GSSG:GSH x 100 ratio was significantly higher in young DS patients (< 15 years), in contrast to DS patients aged >or=15 years that showed a significant decrease in the GSSG:GSH x 100 ratio ratio vs. controls of the respective age groups. Plasma Glx levels were significantly higher in young DS patients, whereas no significant difference was detected in DS patients aged >or=15 years. Unlike Glx, the plasma levels of MGlx were found to be significantly lower in DS patients vs. controls. A significant increase was observed in plasma levels of UA in DS patients that could be related to an increased plasma XO activity in DS patients. The plasma concentrations of AA were also increased in young (< 15 years) DS patients, but not in older patients vs. controls in the same age range. The levels of Vitamin E in DS patients did not differ from the values determined in control donors. The evidence for a multiple pro-oxidant state in young DS patients supports the role of oxidative stress in DS phenotype, with relevant distinctions according to patients' ages.